Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (3): 680-686.doi: 10.4103/1673-5374.380908

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Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Jie Wu1, 2, 3, #, Yulei Huang4, #, Hanrui Yu4, #, Kaixiu Li4, Shifeng Zhang4, Guoqing Qiao4, Xiao Liu5, Hongmei Duan5, Yifei Huang1, Kwok-Fai So6, 7, 8, 9, 10, Zhaoyang Yang5, *, Xiaoguang Li5, 11, 12, *, Liqiang Wang1, 2, *#br#   

  1. 1Department of Ophthalmology, the Third Medical Center, Chinese PLA General Hospital, Beijing, China; 2The PLA Medical College, Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China; 3Department of Ophthalmology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan Province, China; 4Medical School of Chinese PLA, Beijing, China; 5Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; 6Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, Guangdong Province, China; 7Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong Province, China; 8Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong Special Administrative Region, China; 9Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, Guangdong Province, China; 10Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; 11School of Engineering Medicine, Beijing Key Laboratory for Biomaterials and Neural Regeneration, Beihang University, Beijing, China; 12Beijing International Cooperation Bases for Science and Technology on Biomaterials and Neural Regeneration, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China
  • Online:2024-03-15 Published:2023-09-02
  • Contact: Liqiang Wang, MD, PhD, liqiangw301@163.com (lead contact); Xiaoguang Li, PhD, lxgchina@sina.com; Zhaoyang Yang, PhD, wack_lily@163.com.
  • Supported by:
    This work was supported by PLA General Hospital Program, No. LB20201A010024 (to LW).

Abstract: Neurotrophic keratopathy is a persistent defect of the corneal epithelium, with or without stromal ulceration, due to corneal nerve deficiency caused by a variety of etiologies. The treatment options for neurotrophic keratopathy are limited. In this study, an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor (CTH-mNGF). Its effectiveness was evaluated in corneal denervation (CD) mice and patients with neurotrophic keratopathy. In the preclinical setting, CTH-mNGF was assessed in a murine corneal denervation model. CTH-mNGF was transparent, thermosensitive, and ensured sustained release of mNGF for over 20 hours on the ocular surface, maintaining the local mNGF concentration around 1300 pg/mL in vivo. Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice. A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy. Patients received topical CTH-mNGF twice daily for 8 weeks. Fluorescein sodium images, Schirmer’s test, intraocular pressure, Cochet-Bonnet corneal perception test, and best corrected visual acuity were evaluated. In total, six patients (total of seven eyes) diagnosed with neurotrophic keratopathy were enrolled. After 8 weeks of CTH-mNGF treatment, all participants showed a decreased area of corneal epithelial defect, as stained by fluorescence. Overall, six out of seven eyes had fluorescence staining scores < 5. Moreover, best corrected visual acuity, intraocular pressure, Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement. An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes. This study demonstrates that CTH-mNGF is transparent, thermosensitive, and has sustained-release properties. Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy, being convenient and cost effective.

Key words: chitosan, corneal reinnervation, murine nerve growth factor, neurotrophic keratopathy, thermosensitive hydrogel